title: New strategies in the development of antidepressants: towards the modulation of neuroplasticity pathways.
abstract: Over the past five decades, the pharmacological treatment of depression has been based on the pathophysiological hypothesis of a deficiency in monoamines, mainly serotonin and noradrenaline. Antidepressant prescribed today, all of them designed to enhance central monoaminergic tone, present several important limitations, including a 2-5 weeks response lag and also a limited clinical efficacy. As it is increasingly evident that the abnormalities associated to depression go beyond monoamines, the development of better antidepressants will depend on the identification and understanding of new cellular targets. In this regard, much evidence supports a role for cellular and molecular mechanisms of neuroplasticity, including neurotrophic inputs, in mood disorders, in parallel with the biological features associated to stress conditions. In order to illustrate the possible relevance of neuroplasticity-related pathways for the therapy of depressive states, we here review the biological evidence supporting some therapeutic strategies in a very initial phase of development (modulation of the Wnt/GSK-3β/β-catenin pathway, potentiation of endocannabinoid activity, agonism of 5-HT(4) receptors), which involve modulation of downstream mechanisms and neuroplasticity circuits. These strategies also show the existence of mixed mechanisms of action, constituting a nexus between the "classic" aminergic theory and the "new" neuroplasticity hypothesis.
authors.affiliation: Instituto de Biomedicina y Biotecnología (UC-CSIC-IDICAN), Santander, Cantabria, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Vidal
authors.forename: Fuencisla
authors.initials: F
authors.lastname: Pilar-Cuéllar
authors.forename: Severiano
authors.initials: S
authors.lastname: dos Anjos
authors.forename: Raquel
authors.initials: R
authors.lastname: Linge
authors.forename: Begoña
authors.initials: B
authors.lastname: Treceño
authors.forename: Verónica Inés
authors.initials: VI
authors.lastname: Vargas
authors.forename: Antonio
authors.initials: A
authors.lastname: Rodriguez-Gaztelumendi
authors.forename: Ricardo
authors.initials: R
authors.lastname: Mostany
authors.forename: Elena
authors.initials: E
authors.lastname: Castro
authors.forename: Alvaro
authors.initials: A
authors.lastname: Diaz
authors.forename: Elsa M
authors.initials: EM
authors.lastname: Valdizán
authors.forename: Angel
authors.initials: A
authors.lastname: Pazos
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D063385:Cannabinoid Receptor Modulators / Q000502:physiology; D003863:Depression / Q000188:drug therapy* / Q000503:physiopathology; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008954:Models, Biological; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D044422:Receptors, Serotonin, 5-HT4 / Q000502:physiology; D058828:Serotonin 5-HT4 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D000928:Antidepressive Agents; D063385:Cannabinoid Receptor Modulators; D058828:Serotonin 5-HT4 Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4